Penetration of 3H Tiazofurin from Blood into Guinea Pig Brain

  • Z. B. Redzic
  • I. D. Markovic
  • S. S. Jovanovic
  • D. M. Mitrovic
  • Lj. M. Rakic
Part of the Advances in Behavioral Biology book series (ABBI, volume 46)

Summary

Transport of tiazofurin (2-β-D-ribofuranosyl thiazole-4-carboxamide) across the blood-brain barrier (BBB) was studied using brain vascular perfusion method in the guinea pig. The obtained results demonstrate that brain clearance of 3H tiazofurin significantly differs from zero, suggesting that this molecule penetrates from blood into the brain. The values of tiazofurin brain clearance are very close to the values obtained for neuropeptides and other so called “slow penetrating molecules” (regarding the blood brain barrier). Addition of increasing concentrations of unlabelled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labelled tiazofurin. Therefore, penetration of tiazofurin from blood into brain seems to be a saturable process. Presence of increasing concentrations of unlabelled adenosine has similar effect as the presence of unlabelled tiazofurin in the perfusing medium. However, it did not cause complete inhibition of tiazofurin brain uptake.

Kinetic parameters of transport, calculated from the experimental data points, suggest that: a) transport of tiazofurin from blood into guinea pig brain is mostly mediated by the nucleosides’ transport system, but another mechanism is also involved in this transport (Kd a>0); b) tiazofurin, compared to adenosine, has very small affinity for nucleoside carriers at luminal side of the guinea pig BBB (Km≫Ki a); c) free diffusion of tiazofurin from blood to brain parenchyma does not exist (Kd≈0).

Perfusion with medium containing low concentration of Na+ (<1mmol/1) did not cause significant decrease in tiazofurin brain uptake. Hence, Na+ — dependent cotransport is probably not involved in tiazofurin brain uptake.

Our results show that TZF transport from blood to the brain could be considered as a complex process which is still to be elucidated in order to improve its therapeutic use.

Keywords

Perfuse Medium Luminal Side Small Affinity Brain Clearance Nonspecific Diffusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Résumé

Nous avons étudié chez le cobaye le transport de la thiazofurine (2-β-D-ribofuranosyl-thiazole-4-carboxamide) à travers la BHE par la méthode perfusion vasculaire cérébrale. Nos résultats montrent que la clairance de la 3H-thiazofurine est nettement différente de zéro, ce qui suggère que cette molécule passe du sang vers le cerveau. Les taux de clairance cérébrale de la thiazofurine sont très voisins de ceux obtenus pour des neuropeptides et d’autres molécules dites „ à pénétration lente “(dans la BHE). L’addition de taux croissants de thiazofurine non marquée au milieu de perfusion provoque une chute significative de la capture de thiazofurine marquée. Cette pénétration du sang vers le cerveau semble donc relever d’un processus saturable; l’effet est le même par addition d’adénosine non marquée, mais sans toutefois aboutir à une totale inhibition de la capture de la thiazofurine marquée.

Les paramètres cinétiques de ce transport, calculés à partir des données expérimentales, suggèrent les conclusions suivantes: a/- chez le cobaye, le transport de la thiazofurine du sang vers le cerveau; est médié essentiellement par un système de transport de nucléosides, mais un autre mécanisme intervient également (Ki d>0); b/- par comparaison avec l’adénosine, la thiazofurine a une très faible affinité pour les transporteurs de nucléosides au niveau de la face luminale de la BHE du cerveau de cobaye (Km ≫Ki d); c/- il n’y a pas de libre diffusion de la thiazofurine du sang vers le parenchyme du cerveau (Kd≅0). La capture cérébrale de thiazofurine n’est pas réduite de façon significative parla perfusion d’un milieu à faible concentration en Na (< 1 mmol/1). Donc le co-transport Na-dépendant n’est sans doute pas impliqué dans la capture cérébrale de la thiazofurine.

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References

  1. 1.
    Szekeres T, Fritzer M, Pillwein K, Felzmann T and Chiba P. Cell cycle dependent regulation of IMP dehydrogenase activity and effect of tiazofurin. Life Sci 1992; 51 (16): 1309–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Yamada Y., Natsumeda Y., Yamaji Y. et al. IMP Dehydrogenasc: Inhibition by the antileukemic drug, tiazofurin. Leuk Res (1989) 13 (2): 179–84.PubMedCrossRefGoogle Scholar
  3. 3.
    Zlokovic BV, Begley D, Durièiæ B and Mitrovia D. M. Measurement of solute transport across the blood brain barrier in the perfused guinea pig brain; method and application to N-methyl-a-amino isobutyric acid. J Neurochem (1986) 46: 1444–1451.PubMedCrossRefGoogle Scholar
  4. 4.
    Redzic Z. B., Markovic I D., Jovanovic S. S., Mitrovic D., M., Zlokovic B. V., Rakic Lj. M. Slow penetration of [3H] tiazofurin into guinea pig brain by a saturable mechanism.(1995). 17(6) (in press).Google Scholar
  5. 5.
    Pardridge W. M., Yoshikawa T., Kang Y. S., Miller L. P. Blood-brain transport and brain metabolism of adenosine and adenosine analogs. J Phannacol Ex)) Ther. (1994) 268 (1): 14–8.Google Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Z. B. Redzic
    • 1
  • I. D. Markovic
    • 2
  • S. S. Jovanovic
    • 2
  • D. M. Mitrovic
    • 1
  • Lj. M. Rakic
    • 1
  1. 1.Institute of BiochemistrySchool of MedicineBelgradeYugoslavia
  2. 2.Biomedical Research DepartmentICN Galenika InstituteBelgradeYugoslavia

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